第三部分
突触传递
突触传递
Kandel-Ch11_0237-0253.indd 237 23/12/20 9:51 AM
10.9.1: 在细胞培养中,机械感觉神经元(中心,绿色)发送其轴突与 2 个运动神经元(红色,橙色)形成兴
奋性突触连接,概括了活体动物中的连接。这些神经元是从加利福尼亚海螺中分离出来的。
在第二部分中,我们研究了电信号是如何在单个神经元内启动和传播的。我们现在转向突触传递,即一
神经细胞与另一个细胞交流的过程。
除了一些例外,突触由 3 个组成部分组成:1)突触前轴突的末端,2)突触后细胞上的靶标,以及(3
并置区。根据并置的结构,突触分为两大类:电突触和化学突触。在电突触中,突触前末端和突触后细胞在称为
间隙连接的区域非常紧密地并置。突触前神经元中动作电位产生的电流通过称为间隙连接通道的特殊桥接通
直接进入突触后细胞,间隙连接通道物理连接突触前和突触后细胞的细胞质。在化学突触上,2 个细胞之间有一
道裂缝,细胞不能通过桥接通道进行交流。相反,突触前细胞的动作电位会导致神经末梢释放化学递质。递质在
突触间隙扩散,并与突触后膜上的受体分子结合,后者调节突触后细胞中离子通道的打开和关闭。这导致突
后神经元的膜电位发生变化,该神经元可以刺激或抑制动作电位的释放。
神经递质的受体可分为两大类,这取决于它们如何控制突触后细胞中的离子通道。一种类型是离子型受体,
它是一种在递质结合时打开的离子通道。第二种类型,代谢型受体,通过激活突触后细胞内的生化第二信使
联,间接作用于离子通道。 2 种类型的受体都可以导致兴奋或抑制。信号的符号不取决于递质的身份,而是取
决于递质与之相互作用的受体的性质。大多数递质都是低分子量分子,但某些肽也可以作为突触的信使。电
理学、生物化学和分子生物学的方法已被用于表征突触后细胞中对这些不同化学信使作出反应的受体。这些
205
突触传递
法还阐明了第二信使通路如何在细胞内转导信号。
在本书的这一部分,我们认为突触传递是最基本的形式。我们首先比较和对比两大类突触,化学突触
突触(见第 11 章)。然后,我们将重点放在外周神经系统中的化学突触模型上,即突触前运动神经元和突触后
骨骼肌纤维之间的神经肌肉接头(见第 12 章)。接下来,我们研究中枢神经系统神经元之间的化学突触重点
是突触后细胞及其对来自多个突触前输入的突触信号的整合,这些信号同时作用于离子型受体(见第 13 章)
代谢型受体(参见第 14 章)然后,我们转向突触前末梢,考虑神经元从突触前末端释放递质的机制,神经活动
如何调节递质的释放(见第 15 章),以及神经递质化学性质(见 16 章)。由于化学突触的分子结构是复杂
的,许多遗传性疾病和获得性疾病都会影响化学突触的传递,我们将在稍后的第 57 章进行详细讨论。
贯穿本节各章以及整本书的一个关键主题是可塑性的概念。在所有突触中,突触连接的强度不是固定的,
是可以通过行为背景或经验,通过被称为突触可塑性的各种机制,以各种方式进行改变。一些修饰是由突触
身的活动引起的同突触可塑性其他修饰取决于外在因素,通常是由于调节递质的释放异突触可塑性
53 章和第 54 章中,我们将看到这种修改如何为不同形式的记忆存储提供胞基质,其持续时间从几秒钟
一生。在第九部分的章节中,我们将看到突触可塑性功能障碍如何导致各种神经疾病和精神疾病。
206
11 突触传递概述
是什么赋予神经细胞以如此精确且快速相互交流的特殊能力?我们已经看到信号是如何在神经元传播的,
从它的树突和细胞体到它的轴突末端。在本章中,我们开始考虑神经之间通过突触传递过程发出的信号。
触传递是我们在本书中讨论的神经功能的基础,例如感知、自主运动和学习。
神经元在称为突触的专门部位相互交流。平均每个神经元形成数千个突触连接并接收相似数量的输入。
而,这个数字可能会因神经元的特定类型而有很大差异。小脑的浦肯野细胞接收多达 10 万个突触输入,而邻近
的颗粒神经元(大脑中数量最多的一类神经元)仅接收 4 兴奋性输入。尽管中枢神经系统和周围神经系统
中的许多突触连接是高度专业化的,但所有神经元都利用突触传递的 2 种基本形式之一:电或化学。此外,2
形式的突触传递的强度不是固定的,而是可以通过神经元活动增强或减弱。这种突触可塑性对于记忆和其他
层大脑功能至关重要。
电突触主要用于发送快速定型去极化信号。相反,化学突触能够发出更多的信号,因此可以产
更复杂的相互作用。它们可以在突触后细胞中产生兴奋性或性作用,并引发突触后细胞持续几毫秒到几
时的变化。化学突触还可放大神经元信号,因此即使是一个小的突触前神经末梢也可以改变大的突触后细
的反应。由于化学突触传递对于理解大脑和行为至关重要,因此将在接下来的四章中对其进行详细研究。
11.1 突触主要是电突触或化学突触
突触一词由查尔斯 · 谢林顿 20 世纪初引入,用于描述一个神经元与另一个神经元通信的专门接触区。19
世纪后期,拉蒙 · 卡哈尔首次在光学显微镜水平上对该部位进行了组织学描述。
所有的突触最初都被认为是通过电传输来运作的。然而,在 20 世纪 20 代,奥托 · 勒维现一种化合物,
很可能是乙酰胆碱可以从迷走神经传递信号以减慢心跳。勒维的发现在 20 世纪 30 年代引发了关于化学信
是否存在于运动神经和骨骼肌之间的快速突触以及大脑突触中的大量争论。
出现了 2 种思想流派,一种是生理学派,另一种是药理学派。每一种流派都支持单一的机制用于所有突触
传递。约翰 · 埃克尔斯谢林顿的学生)的带领下,生理学家认为突触传递是的,突触前神经元中的动作电
位会产生被动流入突触后细胞的电流。亨利 · 戴尔为首的药理学家认为,传递是化学的,突触前神经元中的动
作电位会导致化学物质的释放,而化学物质又会在突触后细胞中启动电流。当生理学和超微结构技术在 20 世纪
50 年代和 60 年代得到改进时,很明显 2 种传播形式都存在。虽然大多数神经元通过化学递质启动电信号,但许
多其他神经元直接在突触后细胞中产生电信号。
一旦用电子显微镜可以看到突触的精细结构,就会发现化学突触和电突触具有不同的结构。在化学突触中,
突触前和突触后神经元被一个小空间完全分开,即突触间隙;一个细胞和下一个细胞的细胞质之间没有连续性。
相反,在电突触处,突触前和突触后细胞通过直接连接 2 个细胞细胞质的特殊通道进行通信。
11.1 结了 2 种突要功性。过将注入细胞去极化,观察
要的差异。在这 2 种类型的突触中,穿过突触前细胞膜的外向电流在其膜内部沉积正电荷,从而使细胞去极化
(第 9 章)在电突触处,一些电流将通过间隙连接通道进入突触后细胞,在膜内部沉积正电荷并使其去极化。
11.1.1A 所示,电流通过静息通道跨膜离开突触后细胞。如果去极化超过阈值,突触后细胞中的电压门控离子
通道会打开并产生动作电位。相比之下,在化学突触处,突触前细胞和突触后细胞之间没有直接的低电阻通路。
相反,如图 11.1.1B 所示,突触前神经元中的动作电位启动化学递质的释放,化学递质扩散穿过突触间隙并与突
触后细胞膜上的受体结合。
11.2 电突触提供快速信号传输
在电突触的兴奋性突触传递过程中,突触前细胞中的电压门控离子通道产生使突触后细胞去极化的电流。
此,这些通道不仅使突触前细胞在动作电位阈值以上去极化,而且产生足够的离子电流以在突触后细胞中产
11.2 电突触提供快速信号传输
11.1: 电突触和化学突触的区别性质
突触类型
突触前和
突触后细胞膜
之间的距离
突触前和
突触后细胞之间
的细胞质连续性
超微结构成分 传输代理 突触延迟 传输方向
4 纳米 间隙连接通道 离子电流 几乎没有 通常是双向
化学 20-40 纳米
突触前小泡
和活动区;
突触后受体
化学递质
显著:至
0.3 毫秒,
通常为 1-5 毫秒
或更长时间
单向
Chapter 11 / Overview of Synaptic Transmission 243
Figure 11–1 Functional properties of electrical and chemical
synapses.
A.At an electrical synapse, some current injected into the
presynaptic cell escapes through resting (nongated) ion channels
in the cell membrane. However, some current also enters the
postsynaptic cell through gap-junction channels that connect the
cytoplasm of the pre- and postsynaptic cells and that provide a
low-resistance (high-conductance) pathway for electrical current.
B.At chemical synapses, all current injected into the
presynaptic cell escapes into the extracellular fluid.
However, the resulting depolarization of the presynaptic
cell membrane can produce an action potential that causes
the release of neurotransmitter molecules that bind recep-
tors on the postsynaptic cell. This binding opens ion chan-
nels that initiate a change in membrane potential in the
postsynaptic cell.
+ +
A 电突触的电流通路
突触后突触前 突触前
B 化学突触的电流通路
突触后
and, according to Ohm’s law V = I × R
in
), undergoes
a greater voltage change V) in response to a given
presynaptic current (I).
Electrical synaptic transmission was first described
by Edwin Furshpan and David Potter in the giant
motor synapse of the crayfish, where the presynaptic
fiber is much larger than the postsynaptic fiber (Figure
11–2A). An action potential generated in the presynap-
tic fiber produces a depolarizing postsynaptic poten-
tial that often exceeds the threshold to fire an action
Figure 11–2 Electrical synaptic transmission was first
demonstrated at the giant motor synapse in the
crayfish.(Adapted, with permission, from Furshpan and Potter
1957 and 1959.)
A.The lateral giant fiber running down the nerve cord is the
presynaptic neuron. The giant motor fiber, which projects from
the cell body in the ganglion to the periphery, is the postsynaptic
neuron. Electrodes for passing current and for recording voltage
are placed within the pre- and postsynaptic cells.
B.Transmission at an electrical synapse is virtually instantaneous
the postsynaptic response follows presynaptic stimulation in
a fraction of a millisecond. The dashed line shows how the
responses of the two cells correspond in time. At chemical
synapses, there is a delay (the synaptic delay) between the
pre- and postsynaptic potentials (see Figure 11–8).
B Electrical synaptic transmission
mV
50
50
100
0
25
0
Postsynaptic
potential
Current pulse
to presynaptic
ber
01234 ms
Current
injection
Postsynaptic
electrode
Presynaptic
electrode
Current
injection
A Experimental setup
Postsynaptic
neuron:
giant motor
ber
Electrical
synapse
Presynaptic neuron:
lateral giant ber
Presynaptic
potential
Pre
Post
Kandel-Ch11_0237-0253.indd 243 23/12/20 9:51 AM
11.1.1
: 电突触和化学突触的功能特性。
A.
电突触
处,一些注入
突触前
细胞的电流通过细胞膜中的静息(非
门控)离子通道逸出。然而,一些电流也通过间隙连接通道进入突触后细胞,间隙连接通道连接突触前细胞
突触后细胞的细胞质,并为电流提供低电阻(高电导)通路。B. 化学突触处,所有注入突触前细胞的电流
会逃逸到细胞外液中。然而,由此产生的突触前细胞膜去极化会产生动作电位,导致释放与触后胞上的
体结合的神经递质分子。这种结合打开离子通道,引发突触后细胞膜电位的变化。
电位变化。要产生如此大的电流,突触前末端必须足够大,以使其膜包含许多离子通道。同时,突触后细胞必须
相对较小。这是因为小细胞比大细胞具有更高的输入电阻R
in
并且根据欧姆定律V = I ×R
in
响应给
定的突触前电流(I,会经历更大的电压变化(V
如图 11.2.1A 所示,电突触传递首先由爱德华 · 斯潘大卫 · 波特小龙虾的巨大运动突触中描述,其中
突触前纤维比突触后纤维大得多。突触前纤维中产生的动作电位会产生去极化的突触后电位,该电位通常超
激发动作电位的阈值。如图 11.2.1B 所示,在电突触处,突触延迟(突触前尖峰和突触后电位之间的时间)非常
短。
化学传递不可能出现如此短的潜伏期,这需要几个生化步骤:从突触前神经元释放递质,递质分子穿过
触间隙扩散到突触后细胞,递质与特定受体的结合,以及随后的门控离子通道(本章和下一章均有描述)只有
电流直接从一个细胞流向另一个细胞才能产生在巨电机电突触处观察到的近乎瞬时的传输。
电传输的另一个特点是突触后细胞电位的变化与突触前细胞电位变化的大小和形状直接相关。如图 11.2.3
示,即使将微弱的亚阈值去极化电流注入突触前神经元,一些电流也会进入突触后细胞并使其去极化。相反,
化学突触中,突触前细胞中的电流必须达到动作电位的阈值,然后才能释放递质并在突触后细胞中引起反应。
大多数电突触可以传输去极化和超极化电流。具有较大超极化后电位的突触前动作电位会在突触后细胞
产生双相(去极化-极化)电位变化。电突触处的信号传输类似于亚阈值电信号沿轴突的被动传播(第 9 章)
因此也称电紧张传输在一些专门的间隙连接处,通道具有电压依赖性门控,允许它们仅在一个方向上传
去极化电流,即从突触前细胞到突触后细胞。这些连接点称为矫正突触(小龙虾的巨型运动突触就是一个例子)
11.2.1 电突触处的细胞通过间隙连接通道连接
在电突触处,突触前和突触后成分并列在间隙连接处,其中 2 个神经元之间的间隔4 纳米)远小于神经元
之间的正常非突触间隙20 纳米)这个狭窄的间隙由间隙连接通道桥接,间隙连接通道是一种特殊的蛋白质结
构,可将离子电流直接从突触前细胞传导至突触后细胞。
208
11.2 电突触提供快速信号传输
Chapter 11 / Overview of Synaptic Transmission 243
Figure 11–1 Functional properties of electrical and chemical
synapses.
A.At an electrical synapse, some current injected into the
presynaptic cell escapes through resting (nongated) ion channels
in the cell membrane. However, some current also enters the
postsynaptic cell through gap-junction channels that connect the
cytoplasm of the pre- and postsynaptic cells and that provide a
low-resistance (high-conductance) pathway for electrical current.
B.At chemical synapses, all current injected into the
presynaptic cell escapes into the extracellular fluid.
However, the resulting depolarization of the presynaptic
cell membrane can produce an action potential that causes
the release of neurotransmitter molecules that bind recep-
tors on the postsynaptic cell. This binding opens ion chan-
nels that initiate a change in membrane potential in the
postsynaptic cell.
+ +
A Current pathways at electrical synapses
PostsynapticPresynaptic Presynaptic
B Current pathways at chemical synapses
Postsynaptic
and, according to Ohm’s law V = I × R
in
), undergoes
a greater voltage change V) in response to a given
presynaptic current (I).
Electrical synaptic transmission was first described
by Edwin Furshpan and David Potter in the giant
motor synapse of the crayfish, where the presynaptic
fiber is much larger than the postsynaptic fiber (Figure
11–2A). An action potential generated in the presynap-
tic fiber produces a depolarizing postsynaptic poten-
tial that often exceeds the threshold to fire an action
Figure 11–2 Electrical synaptic transmission was first
demonstrated at the giant motor synapse in the
crayfish.(Adapted, with permission, from Furshpan and Potter
1957 and 1959.)
A.The lateral giant fiber running down the nerve cord is the
presynaptic neuron. The giant motor fiber, which projects from
the cell body in the ganglion to the periphery, is the postsynaptic
neuron. Electrodes for passing current and for recording voltage
are placed within the pre- and postsynaptic cells.
B.Transmission at an electrical synapse is virtually instantaneous
the postsynaptic response follows presynaptic stimulation in
a fraction of a millisecond. The dashed line shows how the
responses of the two cells correspond in time. At chemical
synapses, there is a delay (the synaptic delay) between the
pre- and postsynaptic potentials (see Figure 11–8).
B
电突触传递
毫伏
50
50
100
0
25
0
突触后电位
触前纤维
的电流脉冲
0123
4 毫秒
电流注入
突触后电极
突触前电极
电流注入
突触后
神经元:
巨运动
纤维
电突触
A 实验设置
突触前神经元:
外侧巨纤维
突触前电位
Kandel-Ch11_0237-0253.indd 243 23/12/20 9:51 AM
11.2.1: 电突触传递首先在小龙虾的巨大运动突触中得到证实
[61-62]
A. 沿着神经索向下延伸的横向巨大纤
是突触前神经元。从神经节内的细胞体向周围突出的巨型运动纤维就是突触后神经元。用于传递电流和记录
压的电极放置在突触前和突触后细胞内。B. 电突触的传输实际上是瞬时的,即突触后反应在几分之一毫秒内
随突触前刺激。虚线显示了 2 个细胞的响应如何及时对应。如图 11.2.2 所示,在化学突触处,突触前电位和突触
后电位之间存在延迟(突触延迟)
Chapter 11 / Overview of Synaptic Transmission 249
to their receptors on the postsynaptic cell membrane.
This in turn activates the receptors, leading to the
opening or closing of ion channels. The resulting flux
of ions alters the membrane conductance and potential
of the postsynaptic cell (Figure 11–8).
These several steps account for the synaptic delay
at chemical synapses. Despite its biochemical com-
plexity, the release process is remarkably efficient—the
synaptic delay is usually only 1 ms or less. Although
chemical transmission lacks the immediacy of electrical
synapses, it has the important property of amplification.
Just one synaptic vesicle releases several thousand
molecules of transmitter that together can open thou-
sands of ion channels in the target cell. In this way, a
small presynaptic nerve terminal, which generates
only a weak electrical current, can depolarize a large
postsynaptic cell.
The Action of a Neurotransmitter Depends on the
Properties of the Postsynaptic Receptor
Chemical synaptic transmission can be divided into
two steps: a transmitting step, in which the presynap-
tic cell releases a chemical messenger, and a receptive
Figure 11–8 Synaptic transmission at chemical synapses
involves several steps.The complex process of chemical syn-
aptic transmission accounts for the delay between an action
potential in the presynaptic cell and the synaptic potential in the
postsynaptic cell, as compared with the virtually instantaneous
transmission of signals at electrical synapses (see Figure 11–2B).
A.An action potential arriving at the terminal of a presynaptic
axon causes voltage-gated Ca
2+
channels at the active zone to
open. The gray filaments represent the docking and release
sites of the active zone.
B.The Ca
2+
channel opening produces a high concentration of
intracellular Ca
2+
near the active zone, causing vesicles contain-
ing neurotransmitter to fuse with the presynaptic cell mem-
brane and release their contents into the synaptic cleft
(a process termed exocytosis).
C.The released neurotransmitter molecules then diffuse across
the synaptic cleft and bind specific receptors on the postsyn-
aptic membrane. These receptors cause ion channels to open
(or close), thereby changing the membrane conductance and
membrane potential of the postsynaptic cell.
突触前动作电位
+40
0
–55
–70
兴奋性
突触后电位
门限
毫伏
Ca
2+
突触前
神经末梢
受体通道
递质
突触后
细胞
Na
+
Na
+
Na
+
–55
–70
门限
1 毫秒
毫伏
ABC
step, in which the transmitter binds to and activates
the receptor molecules in the postsynaptic cell. The
transmitting process in neurons resembles endocrine
hormone release. Indeed, chemical synaptic transmis-
sion can be seen as a modified form of hormone secre-
tion. Both endocrine glands and presynaptic terminals
release a chemical agent with a signaling function, and
both are examples of regulated secretion (Chapter 7).
Similarly, both endocrine glands and neurons are usu-
ally some distance from their target cells.
There is one important difference, however,
between endocrine and synaptic signaling. Whereas
the hormone released by a gland travels through the
blood stream until it interacts with all cells that contain
an appropriate receptor, a neuron usually communi-
cates only with the cells with which it forms synapses.
Because the presynaptic action potential triggers the
release of a chemical transmitter onto a target cell
across a distance of only 20 nm, the chemical signal
travels only a small distance to its target. Therefore,
neuronal signaling has two special features: It is fast
and it is precisely directed.
In most neurons, this directed or focused release is
accomplished at the active zones of synaptic boutons.
Kandel-Ch11_0237-0253.indd 249 23/12/20 9:51 AM
11.2.2: 化学突触的突触传递涉及几个步骤。如 11.2.1B 所示,化学突触传递的复杂过程解释了突触前细胞
中的动作电位与突触后细胞中的突触电位之间的延迟,与电突触处几乎瞬时的信号传递相比。A. 到达突触前轴
突末端的动作电位导致活动区的电压门控 Ca
2+
通道打开。灰色细丝代表活性区的对接和释放位点。B. Ca
2+
通道
开放在活性区附近产生高浓度的细胞内 Ca
2+
,导致含有神经递质的囊泡与突触前细胞膜融合并将其内容物释放
到突触间隙(称为胞吐作用的过程)C. 释放的神经递质分子然后扩散到突触间隙并结合突触后膜上的特定
体。这些受体导致离子通道打开(或关闭),从而改变突触后细胞的膜电导和膜电位。
209
11.2 电突触提供快速信号传输
244 Part III / Synaptic Transmission
potential. At electrical synapses, the synaptic delay—
the time between the presynaptic spike and the post-
synaptic potential—is remarkably short (Figure 11–2B).
Such a short latency is not possible with chemi-
cal transmission, which requires several biochemical
steps: release of a transmitter from the presynaptic
neuron, diffusion of transmitter molecules across the
synaptic cleft to the postsynaptic cell, binding of trans-
mitter to a specific receptor, and subsequent gating of
ion channels (all described in this and the next chapter).
Only current passing directly from one cell to another
can produce the near-instantaneous transmission
observed at the giant motor electrical synapse.
Another feature of electrical transmission is that
the change in potential of the postsynaptic cell is
directly related to the size and shape of the change in
potential of the presynaptic cell. Even when a weak
subthreshold depolarizing current is injected into the
presynaptic neuron, some current enters the postsyn-
aptic cell and depolarizes it (Figure 11–3). In contrast,
at a chemical synapse, the current in the presynaptic
cell must reach the threshold for an action potential
before it can release transmitter and elicit a response in
the postsynaptic cell.
Most electrical synapses can transmit both depolar-
izing and hyperpolarizing currents. A presynaptic action
potential with a large hyperpolarizing afterpotential
produces a biphasic (depolarizing-hyperpolarizing)
change in potential in the postsynaptic cell. Signal trans-
mission at electrical synapses is similar to the passive
propagation of subthreshold electrical signals along
axons (Chapter 9) and therefore is also referred to as
electrotonic transmission. At some specialized gap junc-
tions, the channels have voltage-dependent gates that
permit them to conduct depolarizing current in only
Figure 11–3 Electrical transmission is graded. It occurs
even when the current in the presynaptic cell is below the
threshold for an action potential.As demonstrated by single-
cell recordings, a subthreshold depolarizing stimulus causes a
passive depolarization in the presynaptic and postsynaptic cells.
(Depolarizing or outward current is indicated by an upward
deflection.)
突触前细胞的
电流脉冲
突触前细胞中
记录的电压
突触后细胞中
记录的电压
one direction, from the presynaptic cell to the postsyn-
aptic cell. These junctions are called rectifying synapses.
(The crayfish giant motor synapse is an example.)
Cells at an Electrical Synapse Are Connected by
Gap-Junction Channels
At an electrical synapse, the pre- and postsynaptic
components are apposed at the gap junction, where
the separation between the two neurons (4 nm) is
much less than the normal nonsynaptic space between
neurons (20 nm). This narrow gap is bridged by
gap-junction channels, specialized protein structures
that conduct ionic current directly from the presynap-
tic to the postsynaptic cell.
A gap-junction channel consists of a pair of
hemichannels, or connexons, one in the presynaptic and
the other in the postsynaptic cell membrane. These
hemichannels thus form a continuous bridge between
the two cells (Figure 11–4). The pore of the channel
has a large diameter of approximately 1.5 nm, much
larger than the 0.3- to 0.5-nm diameter of ion-selective
ligand-gated or voltage-gated channels. The large pore
of gap-junction channels does not discriminate among
inorganic ions and is even wide enough to permit
small organic molecules and experimental markers
such as fluorescent dyes to pass between the two cells.
Each connexon is composed of six identical subu-
nits, called connexins. Connexins in different tissues are
encoded by a large family of 21 separate but related
genes. In mammals, the most common connexon in
neurons is formed from the product of connexin 36.
Connexin genes are named for their predicted molec-
ular weight, in kilodaltons, based on their primary
amino acid sequence. All connexin subunits have an
intracellular N- and C-terminus with four interposed
α-helixes that span the cell membrane (Figure 11–4C).
Many gap-junction channels in different cell
types are formed by the products of different con-
nexin genes and thus respond differently to modu-
latory factors that control their opening and closing.
For example, although most gap-junction channels
close in response to lowered cytoplasmic pH or ele-
vated cytoplasmic Ca
2+
, the sensitivity of different
channel isoforms to these factors varies widely. The
closing of gap-junction channels in response to pH
and Ca
2+
plays an important role in the decoupling
of damaged cells from healthy cells, as damaged cells
contain elevated Ca
2+
levels and a high concentration
of protons. Finally, neurotransmitters released from
nearby chemical synapses can modulate the opening
of gap-junction channels through intracellular meta-
bolic reactions (Chapter 14).
Kandel-Ch11_0237-0253.indd 244 23/12/20 9:51 AM
11.2.3: 传输是分级的。即使突触前细胞中的电流低于动作电位的阈值,它也发生。如单细胞记录所示,
亚阈值去极化刺激会导致突触前和突触后细胞发生被动去极化(去极化或外向电流由向上偏转表示)
间隙连接通道由一对半通道或连接子组成,一个位于突触前,另一个位于突触后细胞膜。因此,如图 11.2.4
示,这些半通道在 2 个细胞之间形成了一个连续的桥梁。通道的孔具有约 1.5 纳米的大直径,远大于离子选择性
配体门控或电压门控通道的 0.3 0.5 纳米直径。间隙连接通道的大孔不区分无机离子,甚至足够宽以允许小有
机分子和荧光染料等实验标记物在 2 个细胞之间通过。
每个连接子由 6 个相同的亚基组成,称为连接蛋白。不同组织中的连接蛋白由一个由 21 个独立但相关的基
因组成的大家族编码。在哺乳动物中,神经元中最常见的连接子是由连接蛋白 36 的产物形成的。连接蛋白基因
根据其一级氨基酸序列以其预测分子量(以千道尔顿为单位)命名。如图 11.2.4C 所示,所有连接蛋白亚基都有
一个细胞内 N 端和 C 端,中间有 4 个跨越细胞膜的 α 螺旋。
不同细胞类型中的许多间隙连接通道由不同连接蛋白基因的产物形成,因此对控制其打开和关闭的调节
子有不同的反应。例如,尽管大多数缝隙连接通道会因细胞质 pH 值降低或细胞质Ca
2+
升高而关闭,但不同通道
亚型对这些因素的敏感性差异很大。响应于 pH Ca
2+
的间隙连接通道的关闭在受损细胞与健康细胞的解偶联
中起着重要作用,因为受损细胞含有升高的 Ca
2+
水平和高浓度的质子。最后,从附近的化学突触释放的神经递
质可以通过细胞内代谢反应调节间隙连接通道的开放(第 14 章)
由人类连接蛋白 26 亚基形成的间隙连接通道的三维结构已通过 X 射线晶体学确定。如图 11.2.5 所示,该结
构显示了跨膜 α 螺旋如何组装形成通道的中心孔,以及连接跨膜螺旋的细胞外环如何交叉连接 2 半通道。孔
内衬有促进离子运动的极性残基。N α 螺旋可作为连接蛋白 26 通道的电压门,在关闭状态下堵塞孔的细胞质
口。从功能研究中推断出通道细胞外侧有一个单独的门,由连接前 2 个膜螺旋的细胞外环形成。该环路门被认
为可以关闭未配对到并列细胞中的半通道伙伴的孤立半通道。
11.2.2 电传输允许互连细胞的快速同步激活
电突触有何用处?正如我们所见,电突触传递是快速的,因为它是由细胞之间电流的直接通过引起的。速度
对于逃避反应很重要。例如,金鱼的甩尾反应是由脑干中的一个巨大神经元(称为毛特讷氏细胞介导的,该神
经元在电突触处接收感觉输入。这些电突触使毛特讷氏细胞迅速去极化,进而激活尾巴的运动神经元,从而
速逃离危险。
电传输对于协调神经元组的动作也很有用。因为电流同时穿过所有电耦合细胞的膜,所以几个小细胞可
一起作为一个大细胞。此外,由于细胞之间的电耦合,网络的有效电阻小于单个细胞的电阻。因此,根据欧姆定
律,激发电耦合细胞所需的突触电流大于激发单个细胞所需的突触电流。也就是说,电耦合细胞具有更高的
火阈值。然而,一旦超过这个高阈值,电耦合细胞就会同步放电,因为在一个细胞中产生的电压激活 Na
+
流会非常迅速地传导到其他细胞。
因此,由一组电耦合细胞控制的行为具有重要的适应性优势:它被爆炸性地触发。例如,当受到严重干
时,海兔释放出大量的紫色墨水云,提供保护屏。这种模式化行为是由支配墨腺的 3 个电耦合运动细胞介导
210
11.2 电突触提供快速信号传输
连接子
突触后
细胞质
突触前
细胞质
A
正常细胞外间隙
4
纳米
20
纳米
D
B
每个膜中的孔隙
形成的通道
连接蛋白
突触前
细胞质
胞外空间
用于同源相互作用
的细胞外环
1234
N
C
NTH
用于调节的
细胞质环
C
打开关闭
Figure 11–4 A three-dimensional model of the gap-junction
channel, based on X-ray and electron diffraction studies.
A.The electrical synapse, or gap junction, is composed of
numerous specialized channels that span the membranes of
the pre- and postsynaptic neurons. These gap-junction chan-
nels allow current to pass directly from one cell to the other.
The array of channels in the electron micrograph was isolated
from the membrane of a rat liver cell that had been negatively
stained, a technique that darkens the area around the chan-
nels and in the pores. Each channel appears hexagonal in outline.
Magnification ×307,800.(Reproduced, with permission, from N.
Gilula.)
B.A gap-junction channel is actually a pair of hemichannels,
one in each apposite cell that connects the cytoplasm of the two
cells.(Adapted from Makowski et al. 1977.)
C.Each hemichannel, or connexon, is made up of six identi-
cal subunits called connexins. Each connexin is approximately
7.5 nm long and spans the cell membrane. A single connexin
has intracellular N- and C-terminals, including a short intracel-
lular N-terminal α-helix (NTH), and four membrane-spanning
α-helixes (1–4). The amino acid sequences of gap-junction
proteins from many different kinds of tissue have regions of
similarity that include the transmembrane helixes and the extra-
cellular regions, which are involved in the homophilic matching
of apposite hemichannels.
D.The connexins are arranged in such a way that a pore is
formed in the center of the structure. The resulting connexon,
with a pore diameter of approximately 1.5 to 2 nm, has a
characteristic hexagonal outline, as shown in the photograph
in part A. In some gap-junction channels, the pore is opened
when the subunits rotate approximately 0.9 nm at the cyto-
plasmic base in a clockwise direction.(Reproduced, with per-
mission, from Unwin and Zampighi 1980. Copyright © 1980
Springer Nature.)
Kandel-Ch11_0237-0253.indd 245 23/12/20 9:51 AM
11.2.4: 基于 X 射线和电子衍射研究的间隙连接通道的三维模型。答:电突触或间隙连接由许多跨越突触前和
突触后神经元膜的专门通道组成。这些间隙连接通道允许电流直接从一个细胞传递到另一个细胞。电子显微
片中的通道阵列是从大鼠肝细胞膜中分离出来的,该细胞膜已被负染色,这种技术使通道周围和毛孔中的区
变暗。每个通道的轮廓都是六角形的。放大 307,800 倍。B. 间隙连接通道实际上是一对半通道,每个对应细胞中
都有一个连接 2 个细胞的细胞质
[63]
C. 每个半通道或连接子由 6 个相同的亚基(称为连接蛋白)组成。每个连
接蛋白长约 7.5 纳米,跨越细胞膜。单个连接蛋白具有细胞内 N 端和 C 端,包括短的细胞内 N α 螺旋NTH
4 跨膜 α 螺旋(14。来自许多不同种类组织的间隙连接蛋白的氨基酸序列具有相似区域,包括跨膜螺旋
和细胞外区域,它们参与适当半通道的同嗜性匹配。D. 连接蛋白的排列方式是在结构的中心形成一个孔。由
产生的连接子,孔径约为 1.5 2 纳米,具有特征性的六边形轮廓, A 部分的照片所示。在一些间隙连接通道
中,当亚基在 A 处旋转约 0.9 纳米时,孔被打开细胞质碱基顺时针方向排列
[64]
211
11.2 电突触提供快速信号传输
11.2.5: 间隙连接通道的高分辨率三维结构。所有结构均由人连接蛋白 26 亚基形成的间隙连接通道的 X 射线
晶体学确定。A. 左图:完整的间隙连接通道图,显示了一对并列的半通道。中图:单个连接蛋白亚基的高分
率结构显示 4 个跨膜 α 螺旋14和一个短的 N 末端螺旋NTH亚基的方向对应于右图中黄色亚基的方向。
右图:从细胞质观察半通道的自下而上视图。6 个亚基中的每一个都有不同的颜色。黄色亚基的螺旋被编号。
向对应于左图中黄色半通道的方向,向观察者旋转 90 度。B. 膜平面中间隙连接通道的 2 个侧视图显示 2 个并列
的半通道。方向与 A 部分相同。左:通过通道的横截面显示通道孔的内表面。蓝色表示带正电的表面;红色
示带负电的表面。细胞质入口(漏斗)孔内的绿色物质被认为代表 N 端螺旋形成的通道门。右图:通道的
视图以与 A 部分相同的配色方案显示了 6 个连接蛋白亚基中的每一个。整个间隙连接通道大约 9 纳米宽 x 15
米高。
212
11.3 化学突触可以放大信号
的。如图 11.2.6 所示,一旦超过这些细胞的动作电位阈值,它们就会同步放电。在某些鱼类中,快速的眼球运动
(称为眼跳)也由电耦合运动神经元共同激发所介导。间隙连接在哺乳动物大脑中也很重要,其中电耦合抑制性
中间神经元的同步放电会在大量细胞中产生同步的 40 100 赫兹(伽马)振荡。
Chapter 11 / Overview of Synaptic Transmission 247
at the extracellular side of the channel, formed by the
extracellular loop connecting the first two membrane
helixes, has been inferred from functional studies. This
loop gate is thought to close isolated hemichannels
that are not docked to a hemichannel partner in the
apposing cell.
Electrical Transmission Allows Rapid and
Synchronous Firing of Interconnected Cells
How are electrical synapses useful? As we have seen,
electrical synaptic transmission is rapid because it
results from the direct passage of current between cells.
Speed is important for escape responses. For example,
the tail-flip response of goldfish is mediated by a giant
neuron in the brain stem (known as the Mauthner
cell), which receives sensory input at electrical syn-
apses. These electrical synapses rapidly depolarize the
Mauthner cell, which in turn activates the motor neu-
rons of the tail, allowing rapid escape from danger.
Electrical transmission is also useful for orchestrat-
ing the actions of groups of neurons. Because current
crosses the membranes of all electrically coupled cells
A
B
C
记录
B 运动细胞对尾部刺激的响应
记录
记录
尾部
刺激
释放
墨水
尾部刺激
A
B
C
运动神经元 墨腺感觉神经元
A 着墨响应的神经回路
Figure 11–6 Electrically coupled motor neurons firing
together can produce synchronous behaviors.(Adapted,
with permission, from Carew and Kandel 1976.)
A.In the marine snail Aplysia, sensory neurons from the
tail ganglion form synapses with three motor neurons that
innervate the ink gland. The motor neurons are interconnected
by electrical synapses.
B.A train of stimuli applied to the tail produces a synchronized
discharge in all three motor neurons that results in the release
of ink.
at the same time, several small cells can act together
as one large cell. Moreover, because of the electrical
coupling between the cells, the effective resistance of
the network is smaller than the resistance of an indi-
vidual cell. Thus, from Ohm’s law, the synaptic current
required to fire electrically coupled cells is larger than
that necessary to fire an individual cell. That is, electri-
cally coupled cells have a higher firing threshold. Once
this high threshold is surpassed, however, electrically
coupled cells fire synchronously because voltage-
activated Na
+
currents generated in one cell are very
rapidly conducted to other cells.
Thus, a behavior controlled by a group of electri-
cally coupled cells has an important adaptive advan-
tage: It is triggered explosively. For example, when
seriously perturbed, the marine snail Aplysia releases
massive clouds of purple ink that provide a protective
screen. This stereotypic behavior is mediated by three
electrically coupled motor cells that innervate the ink
gland. Once the action potential threshold is exceeded
in these cells, they fire synchronously (Figure 11–6). In
certain fish, rapid eye movements (called saccades) are
also mediated by electrically coupled motor neurons
Kandel-Ch11_0237-0253.indd 247 23/12/20 9:51 AM
11.2.6: 一起放电的电耦合运动神经元可以产生同步行为
[65]
A. 在海螺海兔中,来自神经节的感觉神
元与支配墨腺 3 运动神经元形成突触。运动神经元通过电突触相互连接。B. 应用于尾巴的一系列刺激会在
所有 3 个运动神经元中产生同步放电,从而导致墨水释放。
除了在神经元信号中提供速度或同步性之外,电突触还可以在细胞之间传递代谢信号。由于其大孔径,
隙连接通道可传导多种无机阳离子和阴离子,包括第二信使 Ca
2+
,甚至可传导中等大小的有机化合物(大 1
kDa 分子量),如第二信使肌醇 1,45-三磷酸(IP
3
环磷酸腺苷,甚至小肽。
11.2.3 间隙连接在胶质细胞功能和疾病中发挥作用
间隙连接在胶质细胞之间以及神经元之间形成。在胶质细胞中,间隙连接介导细胞间和细胞内信号传导。
大脑中,单个星形胶质细胞通过间隙连接相互连接,形成神经胶质细胞网络。脑切片中神经元通路的电刺激
以释放神经递质,从而触发某些星形胶质细胞中细胞内Ca
2+
的升高。这会产生以大约 1-20 微米每秒的速度从星
形胶质细胞传播到星形胶质细胞的Ca
2+
波,比动作电位(10-100 米每秒的传播)慢大约一百万倍。尽管波的确
切功能尚不清楚,但它们的存在表明胶质细胞可能在大脑的细胞间信号传导中发挥积极作用。
间隙连接通道还可以增强某些神经胶质细胞内的交流,例如在周围神经系统中产生轴突髓鞘的施旺细胞
单个施旺细胞成的连续髓鞘层通过间隙连接连接。这些间隙连接可能有助于将髓磷脂层保持在一起,并促
小代谢物和离子穿过多层髓磷脂。施旺细胞隙连接通道的重要性在某些遗传疾病中得到强调。例如,X 染色
体连锁形式的遗传性神经性肌萎缩是一种脱髓鞘疾病,是由破坏连接蛋白 32 功能的单一突变引起的,连接蛋白
32 施旺细胞中表达的基因。遗传性突变会阻止耳蜗中连接蛋白(连接蛋白 26)的功能,该连接蛋白通常形成
对内耳液体分泌很重要的间隙连接通道,占所有先天性耳聋病例的一半。
213
11.3 化学突触可以放大信号
11.3 化学突触可以放大信号
与电突触相反,在化学突触中,突触前神经元和突触后神经元之间没有结构连续性。事实上,化学突触(突
触间隙)处 2 个细胞之间的间隔通常比非突触细胞间隙(20 纳米)稍宽(20-40 纳米)。化学突触传递依赖于神
经递质,神经递质是一种化学物质,可扩散穿过突触间隙并结合并激活靶细胞膜中的受体。如图 11.3.1 所示,
大多数化学突触中,递质从突触前轴突的特殊肿胀中(突触小球)释放出来,通常包含 100 200 个突触小泡,
每个小泡都充满了数千个神经递质分子。
248 Part III / Synaptic Transmission
firing together. Gap junctions are also important in
the mammalian brain, where the synchronous firing
of electrically coupled inhibitory interneurons gener-
ates synchronous 40- to 100-Hz (gamma) oscillations
in large populations of cells.
In addition to providing speed or synchrony in
neuronal signaling, electrical synapses also can trans-
mit metabolic signals between cells. Because of their
large-diameter pore, gap-junction channels conduct a
variety of inorganic cations and anions, including the
second messenger Ca
2+
, and even conduct moderate-
sized organic compounds (<1 kDa molecular weight) such
as the second messengers inositol 1,4,5-trisphosphate
(IP
3
), cyclic adenosine monophosphate (cAMP), and
even small peptides.
Gap Junctions Have a Role in Glial
Function and Disease
Gap junctions are formed between glial cells as well
as between neurons. In glia, the gap junctions medi-
ate both intercellular and intracellular signaling. In
the brain, individual astrocytes are connected to each
other through gap junctions forming a glial cell net-
work. Electrical stimulation of neuronal pathways in
brain slices can release neurotransmitters that trigger
a rise in intracellular Ca
2+
in certain astrocytes. This
produces a wave of Ca
2+
that propagates from astro-
cyte to astrocyte at a rate of approximately 1–20 μm/s,
about a million-fold slower than the propagation of an
action potential (10–100 m/s). Although the precise
function of the waves is unknown, their existence
suggests that glia may play an active role in intercellular
signaling in the brain.
Gap-junction channels also enhance communi-
cation within certain glial cells, such as the Schwann
cells that produce the myelin sheath of axons in the
peripheral nervous system. Successive layers of mye-
lin formed by a single Schwann cell are connected by
gap junctions. These gap junctions may help to hold
the layers of myelin together and promote the passage
of small metabolites and ions across the many layers
of myelin. The importance of the Schwann cell gap-
junction channels is underscored by certain genetic
diseases. For example, the X chromosome–linked form
of Charcot-Marie-Tooth disease, a demyelinating dis-
order, is caused by single mutations that disrupt the
function of connexin 32, the gene expressed in Schwann
cells. Inherited mutations that prevent the function of a
connexin in the cochlea (connexin 26), which normally
forms gap-junction channels that are important for
fluid secretion in the inner ear, underlie up to half of
all instances of congenital deafness.
Chemical Synapses Can Amplify Signals
In contrast to electrical synapses, at chemical synapses,
there is no structural continuity between presynap-
tic and postsynaptic neurons. In fact, the separation
between the two cells at a chemical synapse, the syn-
aptic cleft, is usually slightly wider (20–40 nm) than
the nonsynaptic intercellular space (20 nm). Chemi-
cal synaptic transmission depends on a neurotrans-
mitter, a chemical substance that diffuses across the
synaptic cleft and binds to and activates receptors in
the membrane of the target cell. At most chemical syn-
apses, transmitter is released from specialized swell-
ings of the presynaptic axon—synaptic boutons—that
typically contain 100 to 200 synaptic vesicles, each of
which is filled with several thousand molecules of
neurotransmitter (Figure 11–7).
The synaptic vesicles are clustered at specialized
regions of the synaptic bouton called active zones. Dur-
ing a presynaptic action potential, voltage-gated Ca
2+
channels at the active zone open, allowing Ca
2+
to
enter the presynaptic terminal. The rise in intracellular
Ca
2+
concentration triggers a biochemical reaction that
causes the vesicles to fuse with the presynaptic mem-
brane and release neurotransmitter into the synaptic
cleft, a process termed exocytosis. The transmitter mol-
ecules then diffuse across the synaptic cleft and bind
Figure 11–7 The fine structure of a presynaptic terminal.
This electron micrograph shows an axon terminal in the
cerebellum. The large dark structures are mitochondria. The
many small round bodies are vesicles that contain neurotrans-
mitter. The fuzzy dark thickenings along the presynaptic mem-
brane (arrows) are the active zones, specialized areas that are
thought to be docking and release sites for synaptic vesicles.
The synaptic cleft is the space separating the pre- and post-
synaptic cell membranes. (Reproduced, with permission, from
Heuser and Reese 1977.)
Kandel-Ch11_0237-0253.indd 248 23/12/20 9:51 AM
11.3.1: 突触前末梢的精细结构。这张电子显微照片显示了小脑中的轴突末端。大的深色结构是线粒体。许多
小圆体是含有神经递质的囊泡。沿着突触前膜(箭头)的模糊的深色增厚是活动区,被认为是突触小泡停靠
释放位点的专门区域。突触间隙是分隔突触前和突触后细胞膜的空间。
突触小泡聚集在突触小结的特殊区域,称为活动区。在突触前动作电位期间,活动区的电压门控 Ca
2+
通道
打开,允许 Ca
2+
进入突触前末梢。细胞内 Ca
2+
浓度的升高会引发生化反应,导致囊泡与突触前膜融合并将神经
递质释放到突触间隙中,这一过程称为胞吐作用。然后,递质分子扩散穿过突触间隙并与突触后细胞膜上的
体结合。这反过来会激活受体,导致离子通道的打开或关闭。如图 11.2.2 所示,由此产生的离子通量改变了突触
后细胞的膜电导和电位。
这几个步骤解释了化学突触的突触延迟。尽管其生化复杂,但释放过程非常有效,突触延迟通常只有 1
秒或更短。虽然化学传递缺乏电突触的即时性,但它具有重要的放大特性。仅一个突触小泡就会释放出数千
递质分子,这些递质分子一起可以打开目标细胞中的数千个离子通道。通过这种方式,仅产生微弱电流的小
突触前神经末梢可以使大型突触后细胞去极化。
11.3.1 神经递质的作用取决于突触后受体的特性
化学突触传递可分为 2 个步骤:传递步骤,即突触前细胞释放化学信使;接受步骤,递质结合并激活突触后
细胞中的受体分子。神经元中的传递过程类似于内分泌激素的释放。事实上,化学突触传递可以被视为激素分泌
的一种改良形式。内分泌腺和突触前末梢都释放具有信号功能的化学物质,两者都是调节分泌的例子(第 7 章)
同样,内分泌腺和神经元通常都与其目标细胞有一定距离。
然而,内分泌信号和突触信号之间有一个重要的区别。腺体释放的激素通过血流传播,直到它与包含对
受体的所有细胞相互作用,而神经元通常只与它形成突触的细胞进行交流。由于突触前动作电位会触发化学
质释放到距离仅为 20 纳米的目标细胞上,因此化学信号仅传播一小段距离即可到达其目标。因此,神经元信号
2 个特点:速度快,方向精确。
在大多数神经元中,这种定向或集中释放是在突触神经元的活跃区域完成的。在没有活动区的突触前神
元神经元中,神经元和激素传递之间的区别变得模糊。例如,主神经系统支配平滑肌的神经元与它们的
214
11.4 电突触和化学突触可以共存并相互作用
触后细胞有一定距离,并且在它们的末端没有专门的释放位点。这些细胞之间的突触传递速度较慢,并且依
于更广泛的递质扩散。此外,相同的递质物质可以从不同的细胞中以不同的方式释放。一种物质可以从一个
胞中释放出来,作为一种传统的递质,直接作用于相邻细胞。从其他细胞中,它可以作为调节剂以不那么集中的
方式释放,产生更扩散的作用;从其他细胞中,它可以作为神经激素释放到血液中。
尽管有多种化学物质用作神经递质,包括小分子和肽(第 16 章),但递质的作用取决于识别和结合递质的
突触后受体的特性,而不是递质的化学特性。例如,乙酰胆碱可以激发一些突触后细胞并抑制其他细胞,而在其
他细胞中,它可以同时产生兴奋和抑制。它是决乙酰胆碱用的受体,包括胆碱能突触是兴奋性的还是抑
性的。
在一组密切相关的动物中,一种递质物质与保守的受体家族结合,并且通常与特定的生理功能相关。在
椎动物中,乙酰胆作用于所有神经肌肉接头处的兴奋乙酰胆碱体以触发收缩,同时还作用于抑制性
胆碱受体以减慢心率。
传输过程和接收过程之间的区别不是绝对的;许多突触前终端包含可以修改释放过程的递质受体。在某
情况下,这些突触前受体被从同一突触前末端释放的递质激活。在其他情况下,突触前末梢可以与其他类别
经元的突触前末梢接触,这些神经元释放不同的神经递质。
受体的概念在 19 世纪末由德国细菌学家保罗 · 埃尔利希引入,用于解释毒素和其他药理学试剂的选择性
用以及免疫反应的高度特异性。1900 年,埃尔利希道:“化学物质只能对能够与之建立密切化学关系的组织元素
发挥作用……[这种关系] 必须是特定的。[化学] 基团必须相互适应……就像锁和钥匙一样。
1906
年,英国药理学家约翰兰利假设骨骼肌对箭毒和尼古丁的敏感性是由“接受分子”引起的。受体功能
理论后来由兰利的学生(特别是希勒亨利 · 戴尔发展,该发展基于同时研究酶动力学和小分子与蛋白质之间
的协同相互作用的同步研究。正如我们将在下一章中看到的那样,兰利的“接受分子”已被分离出来,并被定性
为神经肌肉接头的乙酰胆碱受体。
所有化学递质受体都有 2 个共同的生化特征:
1. 它们是跨膜蛋白。暴露于细胞外部环境的区域识别并结合来自突触前细胞的递质。
2. 它们在靶细胞内执行效应器功能。受体通常影响离子通道的打开或关闭。
11.3.2 突触后受体的激活直接或间接地控制了离子通道
神经递质直接或间接控制突触后细胞离子通道的开放。这两类递质作用是由来自不同基因家族的受体蛋
介导的。
直接控制离子通道的受体,例如神经肌肉接头处乙酰胆受体, 4 个或 5 个亚基组成,形成一个大
子。如图 11.3.2A 所示,此类受体既包含形成递质结合位点的细胞外结构域,又包含形成离子传导孔的跨膜结构
域。这种受体通常被称为离子型受体,因为该受体直接控制离子通量。结合神经递质后,受体会发生构象变化,
从而打开离子通道。第 12 章和第 13 章详细讨论了离子型受体(也称为受体通道或配体门控通道)的作用。
间接门控离子通道的受体,如大脑皮层神经元中的几种去甲肾上腺素或多巴胺受体,通常由 1 个或至多 2
亚基组成,它们与其调节的离子通道不同。这些受体通常具有 7 个跨膜 α-螺旋,通过改变细胞内代谢反应发挥
作用,通常被称为促代谢受体。这些受体的激活通常会刺激第二信使的产生,即小型可自由扩散的细胞内代
物,例如环磷酸腺或甘油二酯。在这些第二信使中的许多能激活蛋白激酶,这些酶可以磷酸化不同底物蛋
的酶。如图 11.3.2B 所示,在多数情况下,蛋白激酶直接磷酸化离子通道,包括间隙连接通道和离子型受体,
节它们的打开或关闭。第 14 章详细研究了促代谢受体的作用。
离子型和代谢型受体具有不同的功能。离子型受体产生仅持续几毫秒的相对快速的突触动作。这些通常
于介导快速行为的神经回路的突触中发现,例如牵张受体反射。促代谢受体产生较慢的突触动作,持续数百
秒到几分钟。这些较慢的动作可以通过改变神经元的兴奋性和介导行为的神经回路中突触连接的强度来调节
为。这种调节性突触动作通常在学习过程中充当重要的强化途径。
215
11.4 电突触和化学突触可以共存并相互作用
Chapter 11 / Overview of Synaptic Transmission 251
the production of second messengers, small freely
diffusible intracellular metabolites such as cAMP or
diacylglycerol. Many of these second messengers acti-
vate protein kinases, enzymes that phosphorylate differ-
ent substrate proteins. In many instances, the protein
kinases directly phosphorylate ion channels, includ-
ing gap-junction channels and ionotropic receptors,
modulating their opening or closing (Figure 11–9B).
The actions of metabotropic receptors are examined in
detail in Chapter 14.
Ionotropic and metabotropic receptors have differ-
ent functions. The ionotropic receptors produce rela-
tively fast synaptic actions lasting only milliseconds.
These are commonly found at synapses in neural cir-
cuits that mediate rapid behaviors, such as the stretch
receptor reflex. The metabotropic receptors produce
slower synaptic actions, lasting hundreds of millisec-
onds to minutes. These slower actions can modulate a
behavior by altering the excitability of neurons and the
B 间隔门控
细胞外侧
递质通道
A 直接门控
受体
细胞质侧
氨基末端
羧基末端
G 蛋白
受体
环磷酸腺苷
三磷酸
鸟苷
腺苷酸
环化酶
氨基末端
羧基末端
细胞外侧
细胞质侧
通道
蛋白激酶A
效应
功能
αγαδβ
P
P
P
P
Figure 11–9 Neurotransmitters open postsynaptic ion chan-
nels either directly or indirectly.
A.A receptor that directly opens ion channels is an integral part
of the macromolecule that also forms the channel. Many such
ligand-gated channels are composed of five subunits, each of
which is thought to contain four membrane-spanning α-helical
regions.
B.A receptor that indirectly opens an ion channel is a distinct
macromolecule separate from the channel it regulates. In one
large family of such receptors, the receptors are composed
of a single subunit with seven membrane-spanning α-helical
regions that bind the ligand within the plane of the mem-
brane. These receptors activate a guanosine triphosphate
(GTP)–binding protein (G protein), which in turn activates a
second-messenger cascade that modulates channel activity. In
the cascade illustrated here, the G protein stimulates adenylyl
cyclase, which converts adenosine triphosphate (ATP) to cyclic
adenosine monophosphate (cAMP). The cAMP activates the
cAMP-dependent protein kinase (PKA), which phosphorylates
the channel (P), leading to a change in opening.
strength of the synaptic connections in the neural cir-
cuit that mediates the behavior. Such modulatory syn-
aptic actions often act as crucial reinforcing pathways
in the process of learning.
Electrical and Chemical Synapses
Can Coexist and Interact
As we now realize, both Henry Dale and John Eccles
were correct about the existence of chemical and elec-
trical synapses, respectively. Furthermore, we now
know that both forms of synaptic transmission can coex-
ist in the same neuron and that electrical and chemical
synapses can modify each other’s efficacy. For exam-
ple, during development, many neurons are initially
connected by electrical synapses, whose presence helps
in the formation of chemical synapses. As chemical
Kandel-Ch11_0237-0253.indd 251 23/12/20 9:51 AM
递质
效应功能
11.3.2: 神经递质直接或间接打开突触后离子通道。A. 直接打开离子通道的受体是形成通道的大分子的组成部
分。许多此类配体门控通道由 5 个亚基组成,每个亚基被认为包含 4 个跨膜 α 螺旋区域。B. 间接打开离子通道
的受体是独立于它调节的通道的独特大分子。在此类受体的一个大家族中,受体由一个亚基组成,该亚基具有 7
个跨膜 α 螺旋区域,可在膜平面内结合配体。这些受体激活三磷酸鸟苷结合蛋,后者又激活调节通道活动的
第二信使级联。在这里所示的级联中,G 蛋白刺激腺苷酸环化酶,将三磷酸腺苷转化为环磷酸腺苷环磷酸腺苷
激活环磷酸腺苷依赖性蛋白激酶 A,后者使通道(P)磷酸化,导致开口发生变化。
216
11.4 电突触和化学突触可以共存并相互作用
11.4 电突触和化学突触可以共存并相互作用
我们现在意识到,亨利 · 戴尔埃克尔斯分别对化学突触和电突触的存在都是正确的。此外,我们现在知道
2 种形式的突触传递可以共存于同一个神经元中,并且电突触和化学突触可以改变彼此的功效。例如,在发育过
程中,许多神经元最初由电突触连接,电突触的存在有助于化学突触的形成。随着化学突触开始形成,它们通常
会启动电传输的下调。
2 种类型的突触也可以共存于成熟神经系统的神经元中。 2 突触的作用可能在视网膜回路中可能是最
容易理解的。在那里,杆状和锥状光受体释放神经递质谷氨酸,并在一类称为双极细胞的中间神经元上形成
学突触。每个双极细胞水平延伸其树突,接收来自许多覆盖的视杆细胞和视锥细胞的化学突触输入,这些视
细胞和视锥细胞对来自视野非常小区域的光作出反应。然而,双极神经元的感受野大约是它接收化学突触输
的光受体感受野的 2 倍。这是相邻双极细胞之间以及双极细胞与第二种中间神经元(无长突细胞)之间形成电
突触的结果(第 22 章)
最后,通过不同的蛋白激酶对缝隙连接的效力进行磷酸化可以调节缝隙连接的效力,这通常会增强间隙
接耦合。例如,多巴胺和其他递质可以通过作用于代谢型 G 蛋白偶联受体来调节环磷酸腺苷水平,从而增强
降低通道磷酸化,从而增加或减少间隙连接偶联。这种复杂的信号循环是许多神经回路的标志,并极大地扩
了它们的计算能力。
11.5 亮点
1. 神经元通过 2 种主要机制进行交流:突触传递和化学突触传递。
2. 电突触形成于称为间隙连接的紧密并列区域,它为电荷在通信神经元的细胞质之间流动提供了直接通路,
使电荷能够在沟通神经元的细胞质之间流动。这导致非常快速的突触传递,适用于同步神经元群的活动。
3. 电突触处的神经元通过间隙连接通道连接,间隙连接通道由一对称为连接子的半透明通道形成,每个半
通道由突触前和突触后细胞贡献。每个连接子都是一个六聚体,由 6 个称为连接蛋白的亚基组成。
4. 在化学突触处,突触前动作电位通过胞吐作用触发突触前细胞释放化学递质。然后递质分子迅速扩散穿
过突触间隙,结合并激活突触后细胞中的递质受体。
5. 虽然比电突触传递慢,但化学传递允许通过释放数万个递质分子和激活突触后细胞中成百上千个受体来
放大突触前动作电位。
6. 有两大类传递受体。离子型受体是配体门控离子通道。递质与细胞外结合位点的结合会触发构象变化,
开通道孔,产生离子电流,根据受体的不同,激发(去极化)或抑制(超极化)突触后细胞。离子型受体是快速
化学突触传递的基础,可介导神经系统中的快速信号传递。
7. 促代谢受体负责第二大类化学突触作用。这些受体激活细胞内代谢信号通路,通常会导致第二信使的合
成,例如调节蛋白质磷酸化水平的环磷酸腺苷促代谢受体是慢型、调节突触动作的基础,这些动作有助于行为
状态和唤醒的变化。
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